Histone lactylation bridges metabolic reprogramming and epigenetic rewiring in driving carcinogenesis: Oncometabolite fuels oncogenic transcription

Abstract Heightened lactate production in cancer cells has been linked to various cellular mechanisms such as angiogenesis, hypoxia, macrophage polarisation and T‐cell dysfunction. The lactate‐induced lactylation of histone lysine residues is noteworthy, as it functions as an epigenetic modification that directly augments gene transcription from chromatin. This epigenetic modification originating from lactate effectively fosters a reliance on transcription, thereby expediting tumour progression and development. Herein, this review explores the correlation between histone lactylation and cancer characteristics, revealing histone lactylation as an innovative epigenetic process that enhances the vulnerability of cells to malignancy. Moreover, it is imperative to acknowledge the paramount importance of acknowledging innovative therapeutic methodologies for proficiently managing cancer by precisely targeting lactate signalling. This comprehensive review illuminates a crucial yet inadequately investigated aspect of histone lactylation, providing valuable insights into its clinical ramifications and prospective therapeutic interventions centred on lactylation.


INTRODUCTION
In the past, lactate was primarily regarded as an outcome of energy metabolism; nevertheless, its distinctive biological significance has been progressively comprehended subsequent to the identification of the Warburg effect. 1 As a result of increased glycolytic levels, lactate plays various roles in promoting cancer, such as being used as a source of energy metabolism, participating in signal transduction pathways, regulating the tumour microenvironment (TME) and immune cells, and regulating specific enzyme modifications. 2,38][9] The alterations, which have the ability to be passed down and undone, have a significant impact on the specific control of cellular characteristics. 10,113][14] Significantly, the disturbance of epigenetic alterations and metabolic pathways is frequently linked to various illnesses, and the interaction between metabolism and chromatin presents numerous prospects for therapeutic interventions. 15,16ecognising the interaction between metabolic remodelling and dynamic histone tuning is of utmost importance as it is currently in its early stages.The purpose of this review is to combine current information on the influence of lactate and histone modification on tumour and related gene regulation.Furthermore, we have clarified the scientific significance of future studies on histone alteration and recognised the obstacles that must be tackled, thus opening up new possibilities in the realm of cancer management through epigenetic/metabolic therapies. [22]

Warburg effect
For the aerobic respiration, pyruvate derived from glucose is transported into the mitochondria and undergoes conversion to acetyl-CoA.2][33] Instead of entering the TCA cycle, the pyruvate molecules are converted to lactate through the catalytic activity of cytosolic lactate dehydrogenases (LDHs). 34n 1956, Otto Heinrich Warburg made the seminal observation that substantial lactate production occurs from glucose, particularly in tumour cells, a phenomenon now referred to as the Warburg effect. 19,357][38][39] In addition, glycolysis generates intermediate compounds that aid in the synthesis of nucleotides, proteins and fats, regardless of changes in oxygen concentrations. 402][43] In conclusion, improved glycolysis promotes increased lactate generation, resulting in the acidification of the cellular surroundings.
To support their growth, survival, proliferation and longterm maintenance, cancer cells undergo this metabolic reprogramming. 44,457][48][49] Furthermore, hypoxia plays a crucial role in promoting glycolysis and inhibiting OXPHOS, which is frequently observed in cancerous tissues.These aforementioned observations emphasise the role of lactate signalling in the development of tumours. 31,50

Lactate production and elimination
2][53] Importantly, the buildup of lactate in the human organism presents a higher danger in contrast to the buildup of alternative molecular energy sources, since elevated levels of lactate in the bloodstream can lead to lactic acidosis. 42,54he enzymatic activity of pyruvate dehydrogenase (PDH) The correlation between histone lactylation and the interconnection of epigenetic remodelling and metabolic reprogramming during the progression of cancerous development.Metabolic disorders are visually represented in red, while epigenetic rewiring is depicted in green.
6][57][58] Moreover, the buildup of lactate has the potential to trigger gluconeogenesis in cells of the liver and skeletal muscle.][61] Furthermore, alongside glycolysis, the process of glutamine catabolism serves as an additional approach for cancer cells to produce lactate. 61][64] Afterwards, the transformation of glutamate into αketoglutarate takes place via the enzymatic activity of glutamate dehydrogenase or a cluster of transaminases. 65,66uring this process, carbon obtained from glutamine is converted into oxaloacetate, which is then changed into malate and leaves the mitochondria to be further converted into NADPH and pyruvate. 67,68

Lactate sensing, shuttling and signalling
Importantly, the transportation and detection of lactate rely on the utilisation of monocarboxylate transporter (MCT) and sodium MCT families, along with G protein-coupled receptors (GPRs) called GPR81 and GPR132. 69In cancer cells, glutamine serves as a vital carbon skeleton for the production of lactate and acts as an additional pathway for generating lactate.Out of the 14 recognised MCTs, MCT1-4 are present in different body tissues and play a role in the catalytic coupling of protons and the two-way movement of monocarboxylic acid. 70nder physiological conditions, the combined functioning of MCT1-4 facilitates the transfer of lactate between cells that undergo glycolysis and those that undergo oxidation, playing a crucial role in maintaining lactate balance in various tissues. 71The MCT1 with strong affinity helps maintain balance of lactate by facilitating the movement of lactate across the cell membrane in response to the transmembrane lactate gradient. 72Tumour cells and other cells with elevated levels of lactate within rely on MCT4, which has a low affinity for transporting lactate.The transportation process starts by attaching unbound protons to MCT, then proceeds with the attachment of lactate, which experiences a structural alteration inside the carrier and is subsequently released on the opposite side of the membrane. 30,73Lactate is released prior to the release of protons.5][76][77] The transport of lactate, enabled by MCTs, creates internal links, and has a vital function in the collaborative metabolism of glycolytic cancer cells and oxidative cancer cells, ultimately aiding in the onset and advancement of tumours. 78lassical metabolites have the ability to initiate direct signalling via GPRs. 79Upon the binding of an agonist, the G protein-coupled receptor (GPCR) alpha subunit undergoes a GDP-GTP exchange.Secondary messengers such as cyclic adenosine monophosphate (cAMP) and Ca 2+ play a role in the following signalling events, and their variation depends on the specific alpha subunit type. 80,81Notably, lactate is capable of signalling through GPR81 and GPR132, both of which are sensitive to protons. 82PR81 is detected in different tumours obtained from patients and cancer cell lines.In vivo studies have demonstrated a correlation between levels of GPR81 and tumour growth and metastasis in pancreatic cancer, with a significant decrease observed upon silencing of GPR81. 83rucially, lactate has been shown to actively promote the formation of new blood vessels by activating the phosphoinositide 3-kinase/Akt (PI3K/Akt)-cAMP-CREB (cAMP response element-binding protein) pathway, resulting in the production of pro-angiogenic amphiregulin in breast cancer. 84,85Moreover, lactate has been found to impede the efficiency of anti-cancer immune response by communicating through GPR81 in dendritic cells that invade tumours, thereby compromising their capacity to effectively showcase antigens to T cells by reducing the expression of major histocompatibility complex class II (MHC-II) molecules. 86Furthermore, GPR132 is detected in different body tissues, including the respiratory system, digestive system and immune cells, specifically macrophages. 879][90] The expression of GPR132 exhibits a positive correlation with the existence of M2 macrophages and the incidence of metastasis. 91(Figure 2)

THE ROLE OF HISTONE LACTYLATION
While the significance of lactate as a catalyst for oncogenic signalling has been established, its role in transcriptional regulation remains uncertain.Notably, substantial evidence supports the crucial function of lactate in aiding the alteration of histone lysine residues.This alteration, such as other modifications of histones, plays a role in the regulation of transcriptional activation. 19[94]

Histone lactylation and metabolic reprogramming
The regulation of lactylation by lactate has recently been established as a novel factor influencing the epigenetic landscape. 18,26This discovery not only paves the way for comprehensive investigations into lactate metabolism but also provides crucial points of interest for future studies on functionality and mechanisms.Enhanced glycolysis and the accumulation of lactate are commonly observed in various types of cancer. 47,73,85This metabolic shift leads to the intracellular production of lactate, which has been found to drive a recently discovered PTM known as lysine lactylation on core histones.A recent investigation performed worldwide lactylome profiling on a group of hepatitis B virus-related hepatocellular carcinoma (HCC) and nearby liver tissues that were collected in advance. 95y conducting an integrative analysis of lactylome and proteome, a grand total of 9275 Kla sites were discovered, out of which 9256 sites were found on proteins other than histones.The results suggest that Kla is a widespread alteration that goes beyond histone proteins and the regulation of transcription.Notably, Kla demonstrates a predilection for influencing enzymes involved in diverse metabolic pathways, including the TCA cycle, as well as carbohydrate, amino acid, fatty acid and nucleotide metabolism. 95oreover, in the framework of the pulmonary hypertension (PH) model, Chen et al. observed an augmentation of histone lactylation on hypoxia inducible factor 1 alpha (HIF-1α) targets, namely Bmp5, Trpc5 and Kit, which subsequently stimulates the proliferation of pulmonary artery smooth muscle cells (PASMCs).Furthermore, the use of a LDH inhibitor as a pharmacological treatment led to a decrease in histone lactylation, which ultimately enhanced the proliferation of PASMC and vascular remodelling in hypoxic PH rats. 96urthermore, recent research indicates that metabolic adaptation is a crucial characteristic and requirement for the transition of macrophage phenotype. 89,97Pyruvate kinase M2 (PKM2) is a fundamental molecular factor in the metabolic adaptations of pro-inflammatory macrophages. 98,99The regulation of PKM2 is primarily influenced by PTMs.Specifically, lactylation of PKM2 hinders its transformation from a tetramer to a dimer, thereby enhancing its pyruvate kinase activity and decreasing its nuclear distribution. 100In summary, these findings emphasise the significance of lactylation as a key initiator of metabolic adjustments in diversified pathological events.

F I G U R E 2
The illustration of the Warburg effect elicits an elevation in lactate levels, which is associated with multiple cancer-related traits inclding enhanced signalling for cell proliferation, evasion of growth inhibitory factors, activation of invasion and metastasis, heightened capacity for angiogenesis, evasion of immune system destruction and facilitation of replicative immortality.
F I G U R E 3 Oncogenic functions of histone lactylation in metabolic reprogramming, immunological remodelling, cell senescence and stemness maintenance.
In addition, the involvement of histone lactylation has been suggested in the control of diverse forms of chemical alterations.For instance, Yu et al. noticed a connection between increased amounts of histone Kla and an adverse outlook in individuals with ocular melanoma.The strong positive correlation between ocular melanoma and intracellular histone Kla was further confirmed through the subsequent inhibition of histone Kla in ocular melanoma cells.Melanoma development is caused by the increase in YTHDF2 expression, which is achieved by enhancing histone Kla at the promoter region.YTHDF2, an m6A reader, plays a crucial part in enhancing the development of ocular melanoma. 94While certain observations endorse the concept that histone Kla is crucial for the proliferation of tumours, alternative studies argue that histone Kla lacks the ability to convert healthy cells into cancerous ones.This suggests that histone Kla plays a role in facilitating the growth of developing tumours rather than initiating tumourigenesis initially. 15,20

Histone lactylation and immunological remodelling
Lactic acid, a substance produced during metabolism by both the host and intestinal microbiota, has been recognised as a crucial signalling molecule in the immune system. 69,101Notably, Sun et al. successfully engineered Saccharomyces cerevisiae to produce lactic acid from glucose instead of ethanol, resulting in a high production yield.The application of this genetically modified strain of S. cerevisiae has been shown to effectively alleviate dextran sulfate sodium (DSS)-induced colitis in mice through the inhibition of macrophage pyroptosis and modulation of the intestinal microbiota.This approach holds great potential as a safe and promising therapeutic strategy for the treatment of ulcerative colitis.Howbeit, additional research is needed to determine whether this engineered S. cerevisiae strain is also involved in tumourigenesis, particularly in the context of autoimmune diseases. 102he rapid advancements in genomics and immunology have led to the emergence of immunotherapy as a groundbreaking therapeutic approach for tumour treatment.Immune checkpoint inhibitors, in particular, have demonstrated remarkable efficacy in various tumour types. 19,40Histone lactylation was initially discovered in the macrophages present in the TME, which aligns with the observed high glucose uptake in this specific subpopulation. 5Furthermore, the increased histone lactylation originating from tumours contributes to the polarisation of M2 tissue-associated macrophages, thereby promoting immunological evasion during the progression of cancer. 100,103,104ecently, histone lactylation is also involved in the response towards immunotherapy.For instance, the promotion of increased lactate accumulation facilitated the nuclear translocation of E3BP, a component of the PDH complex.It is worth noting that E3BP demonstrated the capacity to interact with lactylated histone, leading to significant histone lactylation and ultimately resulting in the upregulation of programmed death-ligand 1 (PD-L1) transcription.This finding emphasises the significance of nuclear translocation of metabolic enzymes in connecting histone lactylation and PD-L1-mediated T-cell exhaustion. 21Furthermore, the timely activation of reparative signals is necessary for the resolution of inflammation and the initiation of cardiac repair following myocardial infarction.The lactylation of histones facilitates the early activation of the reparative transcriptional response in monocytes, which is crucial for maintaining immune balance and initiating timely cardiac repair after myocardial infarction. 105n addition to its essential role in histone lactylation, non-histone lactylation has been established as a significant mediator in immunological remodelling.A noteworthy illustration of this phenomenon is observed in hepatocyte HSPA12A, which functions as a novel regulator to protect livers against ischemia-reperfusion (I/R) injury.The inhibition of glycolysis-mediated HMGB1 lactylation and its subsequent secretion from hepatocytes achieves a protective mechanism, which effectively suppresses macrophage chemotaxis and inflammatory activation. 106

Histone lactylation and cell senescence
Cellular ageing plays a crucial role in the progression of age and is closely linked to various age-related ailments, such as Alzheimer Disease (AD), retinopathies and tumours. 50Comparatively higher concentrations of lactic acid were detected in aged mice and AD mouse models' senescent microglia and hippocampus tissues, when compared to their corresponding counterparts.Moreover, the levels of H3K18 lactylation and Pan-Kla were notably increased in both senescent microglia and hippocampus tissues of naturally aged mice as well as AD modelling mice.The results suggest that focusing on this pathway may be a viable approach to slow down the ageing process and delay the onset of AD by reducing the effects of the senescence-related secretory phenotype. 100,107air follicle stem cells (HFSCs) undergo rapid activation and division during a new hair cycle.The quiescence of HFSCs is regulated by various intrinsic and extrinsic mechanisms as individuals age.HFSCs employ glycolytic metabolism and exhibit higher lactate production compared to other epidermal cells.Moreover, lactate generation plays a crucial role in the activation of HFSCs, as evidenced by the prevention of their activation upon deletion of LDH.While this study primarily focuses on the involvement of lactate in HFSC activation, further investigation is needed to explore the role of lactylation in successive studies. 108urthermore, it is important to note that the microenvironment within cancerous tissues exhibits immunosuppressive and pro-tumourigenic characteristics, often characterised by elevated levels of senescence-associated secretory phenotype factors across various cancer types. 109n contrast, tissues impacted by chronic inflammatory diseases exhibit a pro-inflammatory milieu that impedes the resolution mechanisms. 87Despite the divergent immuno-logical conditions, the metabolic profiles within the tissue microenvironments of cancer and inflammatory diseases are analogous: both are characterised by hypoxia, heightened lactate levels and other metabolic by-products, as well as diminished nutrient levels. 110,111While several studies have suggested the substantial involvement of ageing in tumourigenesis, the precise role of histone lactylation remains enigmatic and necessitates further investigation.

Histone lactylation and stemness maintenance
The process of somatic cell reprogramming offers valuable insights into the fundamental mechanisms underlying cell fate determination, particularly in relation to the regulation of stemness. 112,113In a study conducted by Li et al., it was demonstrated that Glis1 directly interacts with chromatin, resulting in the activation of glycolytic genes while repressing somatic genes, ultimately leading to an upregulation of glycolysis.Furthermore, this increased glycolytic activity promotes higher levels of cellular acetyl-CoA and lactate, which in turn enhance acetylation and lactylation at gene loci associated with pluripotency.This process facilitates the opening of these loci, thereby facilitating cellular reprogramming. 114oreover, lactate exhibits the potential to augment the stemness of CD8 + T cells and fortify the immune response directed towards tumours.Examination employing single cell transcriptomics reveals an elevated ratio of CD8 + T cells expressing the stem-like T-cell factor 1 (TCF-1) marker within intra-tumoural CD3 + cells.This characteristic has been corroborated via in vitro lactate treatment of T cells.The effects of lactate are mediated by the inhibition of histone deacetylase activity, resulting in increased acetylation at the H3K27 site of the Tcf7 super enhancer locus.This, in turn, leads to the upregulation of Tcf7 gene expression.Conversely, the modulation of abnormal lactate levels through the inhibition of LDH also promotes the stemness of CD8 + T cells and initiates immune responses against tumours.Collectively, these findings suggest that lactate may play a dual role in regulating the stemness of T cells. 115

CANCER THERAPY TARGETING HISTONE LACTYLATION
During cancerous initiation and progression, lactate has been traditionally regarded as a by-product of aerobic glycolysis in metabolism. 108Nevertheless, an increasing number of studies have indicated that lactate has the ability to control the advancement of cancer through various mechanisms including but not limited to cell cycle control, Examples of targeting lactate metabolism in cancer treatment, including neuroblastoma, lung cancer, hepatocellular carcinoma, etc.
immune system suppression and energy metabolism.The recent discovery of lactylation has attracted considerable attention and has become a prominent topic of conversation in the realm of cancer studies.While several studies have demonstrated the successful therapeutic efficacy of targeting lactate metabolism in various types of cancer (Figure 4 and Table 2), the specific modulation of histone lactylation remains unresolved.

Targeting LDHs for cancer treatment
The LDH enzyme complex, composed of LDHA and LDHB subunits, has five different isoforms that are determined by the combination of LDHA and LDHB subunits. 47The reduction of pyruvate to lactate is catalysed by LDHA, which occurs simultaneously with the regeneration of NAD+.On the other hand, LDHB is responsible for mediating the reverse reaction.Significantly, LDHA is highly expressed in various tumour tissues and is associated with adverse prognostic outcomes in individuals with cancer. 98reclinical trials have evaluated various LDHA inhibitors for their effectiveness.Oxamate, a compound similar to pyruvate and a competitive inhibitor of LDH, hinders the transformation of pyruvate into lactate, thereby affecting cellular glycolysis. 116Studies have recorded that the application of oxamate to lymphoma cells hinders the advancement of acute lymphoblastic leukaemia cells Jurkat and DU528. 117According to records, oxamate has been observed to hinder the growth of cells in nasopharyngeal and gastric cancer. 118Gossypol, FX11 and quinoline 3-sulphonamides are part of the group of LDHA inhibitors that compete with nicotinamide adenine dinucleotide.Several research studies have extensively recorded the effectiveness of these in inhibiting the proliferation of different types of cancer cells, such as those found in the colon, neuroblastoma, HCC, primary pancreatic cancer, melanoma and breast cancer. 118Several specific compounds, such as 1-(phenylseleno)-4-(trifluoromethyl) benzene (PSTMB), phthalimide and dibenzofuran derivatives, have shown the ability to function as LDHA inhibitors, effectively impeding the development and multiplication of cancer cells. 119Particularly noteworthy are the novel LDH inhibitors, phthalimide and dibenzofuran derivatives, which display selective inhibition towards the LDHA isoenzyme. 120Furthermore, recent studies have emphasised the inhibitory properties of small interfering RNAs (siRNAs) targeting LDHA.The investigation into the utilisation of siRNAs to specifically target LDHA with the intention of impeding the progression of cancer by inducing oxidative stress and cell death has demonstrated their potential as a therapeutic strategy for LDHA-dependent malignancies. 121Furthermore, the oncogenic driver Ewing's sarcoma breakpoint region 1-friend leukemia virus integration 1 (EWS-FLI1) in Ewing sarcoma has been observed to impede the proliferation of Ewing sarcoma cells by targeting the transcription of LDHA. 122Consequently, these discoveries provide a solid basis for the advancement of LDHA inhibitors.Nevertheless, the development of more potent and selective compounds remains a significant obstacle that must be overcome to facilitate their clinical application.

Targeting MCTs for cancer treatment
MCTs are members of the solute carrier (SLC) transporter family, which encompasses 52 distinct membrane transporter families.Within this group, MCT1 and MCT4 play a pivotal role in the uptake and release of lactate, as well as the transportation of other monocarboxylates including pyruvate, β-hydroxybutyrate and acetate. 69,123he efficacy of lactate transport is contingent upon the intracellular and extracellular concentrations of lactate, pH levels and the concentrations of other MCT sub-strates.Multiple types of human cancer, including glioma, breast, colorectal, gastric, cervical and neuroblastoma, exhibit heightened expression of MCT1 and MCT4, which has been linked to unfavourable prognostic outcomes. 124nhibition of MCT4 prompts the buildup of intracellular lactate and consequent demise of hypoxic cancer cells.Experimental suppression of MCT4 has demonstrated its essential role in the migratory and invasive capabilities of lung cancer cells. 125Consequently, directing therapeutic efforts towards MCTs holds promise as a viable strategy for cancer treatment.
Numerous MCT blockers have exhibited effectiveness in preclinical experiments.Various malignancies, such as cervical cancer, breast cancer, colorectal cancer, prostate cancer, pharyngeal squamous cell carcinoma and other types of cancer, have been effectively treated using classical inhibitors of MCT1/MCT4, such as quercetin, phloretin and α-cyano4-hydroxycinnamate. 126 Additionally, lonidamine, DIDS, simvastatin and other MCT inhibitors have exhibited therapeutic potential for a range of cancer types. 126,127Additionally, the chaperone protein CD147, which is common to both MCT1 and MCT4, has been observed to promote the migration, invasion and metastasis of cancer cells.Therefore, the targeting of CD147 offers a promising and innovative strategy for suppressing the function of both transporters. 128Notably, p-chloromercuric besylate, an organomercury compound, and AC-73, which selectively hinders CD147 dimerisation, are among the compounds that disrupt MCT binding to CD147.Nevertheless, the clinical utilisation of CD147 is constrained by its involvement as a co-chaperone for other membrane proteins, thereby prompting concerns regarding safety. 129

CONCLUSIONS AND FUTURE DIRECTIONS
Lactate serves as both a terminus of glycolysis and a universal metabolic fuel for energy, as evidenced by the emerging concept of the 'lactate shuttle' facilitating its movement between cells and transmission of signals. 89,95,108he prominence of glycolytic-dependent metabolism in tumours and rapidly proliferating cells has positioned lactate as a crucial participant in the reprogramming of energy metabolism, allowing cells to efficiently acquire ample energy within a limited timeframe. 60,126In addition, lactate has the potential to create advantageous circumstances for the development of tumours through its influence on the acidic microenvironment of the tumour, the recruitment of immune cells, and other mechanisms.
In addition to its fundamental role in accelerating tumourigenesis, histone lactylation also serves as a significant diagnostic marker in various cancers, such as ocular melanoma, 94 colorectal cancer 4 and HCC. 95Notably, elevated levels of global lactylation (pan-lactylation) are specifically upregulated in tumour tissues, indicating a higher likelihood of earlier recurrence and increased aggressiveness in ocular melanomas. 94Furthermore, there is a significant correlation between elevated levels of panlactylation and H3K18la and decreased overall survival rates in individuals diagnosed with colorectal cancer. 4dditionally, it has been observed that HCC patients also exhibit heightened lactylation levels, resulting in the subsequent upregulation of adenylate kinase 2 lactylation.This molecular alteration further promotes the proliferation and metastasis of HCC. 95Cumulatively, these findings substantiate the notion that aberrant histone lactylation is significantly elevated across diverse tumour classifications, thus exerting a pivotal influence on the malignant progression of cancer.Nonetheless, the absence of a comprehensive evaluation regarding the disparity in histone lactylation levels between metastatic sites and primary tumours necessitates further investigation, thereby warranting future exploratory endeavours.
Furthermore, the newly discovered occurrence of lactate-induced lactylation enhances our comprehension of the pro-tumourigenesis consequences of lactate generation, circulation and utilisation. 66,128Analogous to other epigenetic alterations, lactylation possesses the capacity to alter histone proteins, thereby influencing the spatial organisation of chromatin, affecting DNA accessibility and governing the expression of related genes.Moreover, the degree of lactylation is intricately associated with the localised concentration of lactate, establishing a correlation between epigenetics and metabolic reprogramming. 18,19,109ignificantly, this field encounters numerous challenges.Primarily, histone lactylation exhibits shared 'writers' and 'erasers' with other types of histone modifications, rendering the specific modulation of histone lactylation notably difficult.For example, most studies have silenced EP300 to reduce histone lactylation level, which simultaneously reduced the global acetylation levels.Therefore, it is important to find a novel method to specifically modulate global lactate level.Additionally, therapeutic endeavours predominantly focus on multi-functional LDHs and MCTs.Apart from regulating the lactate cascade, these enzymes also exert a crucial influence on other chemical reactions.Consequently, the development of a specific inhibitor targeting histone lactylation necessitates further investigation in our subsequent studies.In addition, the majority of studies substantiate the oncogenic function of histone lactylation in both the initiation and advancement of tumourigenesis.Nevertheless, it is imperative to thoroughly investigate whether histone lactylation may also exert an inhibitory influence on tumour progression, as most modifications exhibit a dualistic impact on carcinogenesis.
In light of the significant role of lactate signalling in diverse cellular processes, it is crucial to conduct thorough investigations into the underlying mechanisms of oncometabolic-mediated epigenetic reprogramming in future research endeavours.Considering that histone lactylation is indicative of an open chromatin state, which is closely associated with super-enhancer and 3Dchromosome architecture, it is warranted to pursue further endeavours aimed at developing a more precise model for epigenetic modulation.By investigating the correlation between histone lactylation and cancer characteristics, we propose that histone lactylation plays a crucial role in predisposing cells to a malignant state, highlighting the significance of identifying innovative therapeutic approaches or dual-targeting methods to combat lactylation for effective cancer management.

C O N F L I C T O F I N T E R E S T S TAT E M E N T
The authors declare no competing financial interests.

D ATA AVA I L A B I L I T Y S TAT E M E N T
All relevant data are available from the authors upon request.
Meili Li and Peirong Lu planned the project.Yu Zhang and Hang Song collected relevant information and clinical samples.All authors analysed the data.Yu Zhang wrote the paper.All authors discussed the results and commented on the manuscript.A C K N O W L E D G E M E N T SThis study was supported by grants from the Suzhou Municipal Health Commission (no.KJXW2020077) and the Science and Technology Program of Suzhou (nos.SKJY2021015 and SYSD2020048).
The role of histone lactylation.
Histone lactylation targeted drugs in cancer therapy.
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